Gastric inhibitory polypeptide (GIP) is an incretin hormone of the secretin family. It was so named because it was originally shown to inhibit histamine-induced gastric acid secretion from innervated canine Bickel-type pouches. However, subsequent studies to elucidate its wider physiological properties established that physiological concentrations of GIP were capable of stimulating insulin secretion from pancreatic beta cells. Thus, the hormone is also known as “glucose-dependent insulinotropic polypeptide”.
Human GIP is a 42 amino acid peptide derived from the processing of a 153 amino acid precursor, whose gene is located on chromosome 17 and spans 10 kb. Incretin hormones are released in response to nutrient ingestion, and act to potentiate the glucose-induced insulin response. GIP is released from intestinal K-cells, and its primary role is to modulate glucose-dependent insulin secretion. GIP can also stimulate proinsulin gene transcription and translation. Furthermore, GIP acts as a beta cell mitogenic factor, enhancing the growth, differentiation and proliferation of pancreatic beta cells. GIP has also been shown to inhibit hepatic glucose production, and to stimulate glucose transport, fatty acid synthesis and lipoprotein lipase activity in adipocytes.
The insulinotropic effect on pancreatic islets, and the glucose-lowering effect in peripheral tissues, makes GIP an attractive candidate as a potential therapeutic agent for the treatment of diabetes, obesity and related metabolic disorders.
Neuroplasticity is a process that involves the continual formation of new neural connections, which occurs during the (re-)organisation of the brain in response to activity and experience. Activity-dependent synaptic plasticity plays a vital role in sculpting synaptic connections during development. However, although well known to occur during development, the process is also a central feature of the adult brain. The plastic nature of neuronal connections allows the brain to continually develop in response to experience, and to circumvent the impaired neuronal signalling that occurs as a consequence of trauma or damage to neurons.
There are two types of modifications that are thought to occur in the brain during this process: 1) morphological changes to the neurons themselves, specifically in the area of the synapse; and 2) an increase in the number of synapses between neurons. The efficiency of synaptic signalling is often dependent on either (or both) of these modifications. Indeed, it is widely accepted that processes such as memory formation and learning ability are dependent on alterations in synaptic efficiency that permit strengthening of associations between neurons. Moreover, synaptic plasticity at certain synapses is thought to be both necessary and sufficient for the process of storing information in the brain.
Long-term potentiation (LTP) has long been proposed as a model for the mechanism by which the strengthening of synaptic connections can be achieved. It has been widely demonstrated that high-frequency stimulation can cause a sustained increase in efficiency of synaptic transmission. Based on this finding, it is believed that the synaptic changes that underpin at least certain forms of learning and memory are similar to those changes required for expression of LTP.
Furthermore, it is widely accepted that impaired LTP is often associated with impaired cognitive function. In this regard, for a number of years now, studies have reported cognitive deficits in aged rats. In particular, aged rats have been shown to exhibit deficits in spatial information processing. Correlated with deficits in performance in spatial learning, was a deficit in LTP in the CA1 region of the rodent brain; wherein severely impaired animals did not sustain LTP, whilst sustained LTP was observed in those animals that were relatively unimpaired in spatial learning.
Therefore, cognitive deficits are a hallmark of a number of neurological disorders. For example, the symptoms of age-related memory impairment are often similar to those symptoms associated with the early stages of neurodegenerative diseases such as Alzheimer's disease. Clearly, a major goal in the field of neuroscience is to sustain LTP in circumstances where LTP is impaired, either by age, disease-associated causes, or by any other instance resulting in impaired synaptic transmission.
However, there is growing evidence that mature neurons may also possess mechanisms to prevent the strengthening of input synapses. Such homeostatic regulation ensures that a neuron operates within an optimal activity range, a process that is integral to maintaining the highly plastic nature of the brain. This is evident in the hippocampus, where pyramidal cells of the CA1 region each receive thousands of excitatory inputs with the potential for activity-dependent enhancement of synaptic transmission. In the absence of a mechanism to limit synaptic strengthening, the physiological balance can be compromised, resulting in the LTP process being shut down, and ultimately leading to a reduced capacity of the entire neuronal circuit for storing information. Therefore, the process of depotentiation also acts as a critical mediator in regulating neuronal homeostasis and ensuring the coordinated control of the strength of synaptic transmission. Depotentiation is now thought to play a role in the removal of redundant information from the memory. As such, depotentiation could act as a potential therapeutic measure in disorders associated with overactive cognitive processes.
It is an object of the present invention to prophylactically prevent, improve, or reverse the diminished cognitive function associated with these types of disorders, by increasing (or sustaining) the LTP of synaptic transmission. Moreover, sustaining LTP may find utility in the prophylaxis of neurological disease by delaying the onset of impaired cognitive processes, and could serve as a treatment, not only for the diminished cognitive function caused by neurodegeneration, but also for the dysfunctional cognitive processes associated with trauma or age. Additionally, it is an object of the present invention to improve the altered cognitive function associated with hyperexcitability-type disorders, by reducing the elevated level of LTP of synaptic transmission.